WO2014117089A1 - Compositions and methods for the treatment of pervasive development disorders - Google Patents

Compositions and methods for the treatment of pervasive development disorders Download PDF

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Publication number
WO2014117089A1
WO2014117089A1 PCT/US2014/013201 US2014013201W WO2014117089A1 WO 2014117089 A1 WO2014117089 A1 WO 2014117089A1 US 2014013201 W US2014013201 W US 2014013201W WO 2014117089 A1 WO2014117089 A1 WO 2014117089A1
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nmdar antagonist
trkb
effective amount
therapeutically effective
subject
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PCT/US2014/013201
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English (en)
French (fr)
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David M. Katz
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Case Western Reserve University
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Priority to EP14743891.5A priority Critical patent/EP2948135B1/de
Priority to EP18212501.3A priority patent/EP3485882A1/de
Priority to US14/763,750 priority patent/US10555916B2/en
Publication of WO2014117089A1 publication Critical patent/WO2014117089A1/en
Priority to HK16105085.7A priority patent/HK1217896A1/zh

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Definitions

  • the present application relates to compositions and methods used for treating pervasive development disorders using NMD A receptor antagonists.
  • Pervasive development disorders refer to a group of disorders characterized by delays in the development of multiple basic functions including socialization and
  • Pervasive developmental disorders include autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood
  • RTT Rett Syndrome
  • MeCP2 methyl-CpG binding protein 2
  • MeCP2 loss of MeCP2 in RTT patients and mouse models is not associated with neuronal cell death or axonal degeneration, although neurons are smaller, more densely packed than normal and exhibit reduced dendritic arborizations, spine density and synapse number.
  • Mecp2 mutant mice exhibit defects in neuronal and synaptic function, including alterations in excitatory/inhibitory (E/I) balance. These microcircuit abnormalities are accompanied by altered expression of neurotransmitters, neurotransmitter synthesizing enzymes, receptors and transporters, as well as molecules required for synapse development.
  • Embodiments described herein relate to compositions and methods of treating pervasive development disorders, such as Rett Syndrome, in a subject.
  • the method includes administering to the subject a therapeutically effective amount of an NMDAR antagonist.
  • the therapeutically effective amount is an amount effective to ameliorate biochemical and functional abnormalities associated with loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MeCP2) in the subject.
  • MeCP2 methyl-CpG binding protein 2
  • therapeutically effective amount of an NMDAR antagonist can be sub-anesthetic.
  • the NMDAR antagonist is selected from the group consisting of Amantadine, AZD6765, Dextrallorphan, Dextromethorphan, Dextrorphan, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine, Gacyclidine, Ibogaine, Memantine, Methoxetamine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine, Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Delucemine, 8A-PDHQ, Aptiganel, HU-211 , Remacemide, Rhynchophylline, Ketamine, 1- Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate' DCKA (5,7- dichlorokynurenic acid), Kyn
  • the method further includes administering to the subject a therapeutically effective amount of a TrkB agonist.
  • the TrkB agonist can be selected from the group consisting of a small molecule, protein and an antibody.
  • the TrkB agonist is an ampakine.
  • the ampakine can include an allosteric modulator of the AMPA- receptor.
  • the NMDAR antagonist can include Remacemide and the TrkB agonist can include N,N,N'Tris(2-hydroxyethyl)-l,3,5-benzenetricarboxamide (LM22A-4).
  • compositions for the treatment of Rett syndrome relate to a pharmaceutical composition for the treatment of Rett syndrome.
  • the composition includes a therapeutically effective amount of an NMDAR antagonist, a therapeutically effective amount of a TrkB agonist, and a
  • the therapeutically effective amount of an NMDAR antagonist and a TrkB agonist can be the amount effective to ameliorate biochemical and functional abnormalities associated with loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MeCP2) in a subject having Rett syndrome.
  • the therapeutically effective amount of an NMDAR antagonist can be sub- anesthetic.
  • the NMDAR antagonist can be selected from the group consisting of Amantadine, AZD6765, Dextrallorphan, Dextromethorphan, Dextrorphan, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine, Gacyclidine, Ibogaine, Memantine, Methoxetamine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine, Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Delucemine, 8A-PDHQ, Aptiganel, HU-211, Remacemide, Rhynchophylline, Ketamine, 1- Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate' DCKA (5,7- dichlorokynurenic acid), Kynure
  • the TrkB agonist can be selected from the group consisting of a small molecule, protein and an antibody.
  • the TrkB agonist is an ampakine.
  • the ampakine can include an allosteric modulator of the AMPA-receptor.
  • the pharmaceutical composition further includes a therapeutically effective amount of a GABAR agonist.
  • FIG. 1 illustrates photographs showing immunostains of reduced Fos expression in forebrain and midbrain structures in symptomatic Mecp2 Null mice.
  • Null mice At 6 weeks of age, Null mice (A3-F4) exhibit markedly reduced levels of Fos expression in a discrete subset of cortical and subcortical structures, including the prelimbic and infralimbic cortices (A), cingulated cortex (B), retrosplenial cortex (C), piriform cortex (D), the nucleus accumbens (E), and periaqueductal gray (F) compared with Wt (A1-F2).
  • FIG. 2 illustrates photomicrographs and graphical illustrations showing increased Fos expression in the hindbrain nTS in symptomatic Mecp2 Null mice. At 6 weeks of age, Null mice exhibit markedly increased levels of Fos expression in subnuclei within the nucleus tractus solitarius (nTS) of the medulla.
  • nTS nucleus tractus solitarius
  • ION Dorsal motor nucleus of vagus
  • 12N hypoglossal nucleus
  • AP area postrema
  • InTS lateral nTS
  • mnTS medial nTS
  • nComm commissural nTS
  • TS tractus solitarius. *p ⁇ 0.05;
  • FIG. 3 illustrates graphical representations of exaggerated evoked synaptic transmission in the adult Null InTS and nComm.
  • A EPSCs evoked in the InTS by low- frequency TS stimulation have significantly larger amplitudes in the Nulls compared with Wt.
  • B Statistical summary of genotype-dependent differences in eEPSC amplitudes in InTS and nComm.
  • C Synaptic depression evoked by 20 Hz stimulus trains is unaffected by Mecp2 genotype.
  • D eEPSC amplitudes averaged across the entire 20 Hz stimulus train are significantly larger in the Null InTS compared with Wt, with a similar trend in nComm.
  • Fig. 4 illustrates graphical representations of enhanced spontaneous excitatory currents at primary afferent synapses in the Null nTS compared with Wt.
  • A Representative recordings from a Wt and a Null InTS second-order neuron illustrating higher sPSC frequency in the Nulls.
  • B Group data reveal a significantly higher sPSC frequency in both Null InTS and nComm compared with Wt.
  • C Representative recordings from a Wt and a Null InTS second order neuron at low (top traces) and high (bottom traces) resolution illustrating higher mEPSC frequency and amplitudes in the Nulls.
  • Fig. 5 illustrates graphical representations of evoked synaptic transmission is normal in the Null nTS at 3 weeks of age despite reduced spontaneous excitatory currents.
  • E Raw traces illustrating reduced mEPSC
  • F frequencyandamplitudesintheNullnTSat3 weeks.
  • G Cumulative mEPSC frequency (F) and amplitude (G) distribution curves demonstrate left shifts in the Nulls at 3 weeks, indicating lower mEPSC frequencies and lower amplitudes, respectively, compared with Wt. *p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.001.
  • Fig. 6 illustrates photomicrographs and graphical illustrations illustrating systemic treatment with ketamine acutely increases Fos expression in the forebrain of Wt and Null mice and reverses the Fos-deficient phenotype in Nulls.
  • A, B Injection of ketamine (100 mg/kg, i.p.) increases Fos expression throughout the forebrain in Nulls and Wt; representative sections from the prelimbic and infralimbic cortices (A) and cingulate cortex (B) are shown.
  • C Ketamine causes a dose-dependent increase in Fos expression levels in Null mice, restoring Fos expression to naive Wt levels as shown here in the piriform cortex. In Wt, 100 mg/kg ketamine increased the number of Fos-positive cells by 20%. *p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.001.
  • Fig. 7 illustrates a graphical illustration of Het mice exhibit abnormal prepulse inhibition of acoustic startle which is restored to Wt levels by acute treatment with a sub- psychotomimetic dose of ketamine. Het mice exhibit a significant increase in PPI amplitude at 11 weeks of age that is restored to Wt levels by acute treatment with ketamine at 8 mg/kg. *p ⁇ 0.05; ***p ⁇ 0.001.
  • Fig. 8 is graphical illustrations of the development of respiratory dysfunction in 8- to 12-week-old Mecp2 " + (Het) mice.
  • Fig. 9 illustrates BDNF protein levels in 8-, 10-, and 12-week-old Mecp2 Het mice.
  • A-C BDNF levels, measured by ELISA, in the NG (A), medulla (B), and pons (C) ofWt (open bars) and Het mice (gray bars).
  • D BDNF immunostaining, representative of 3 Wt and 3 Het littermate pairs, demonstrates reduced BDNF levels in the nTS subregion of the dorsomedial medulla in 12-week-old Het animals compared with Wt. AP, area postrema; tS, tractus solitarius.
  • FIG. 10 is a graphical illustration showing treatment of Mecp2 Het mice with LM22A-4 restores normal respiratory frequency by increasing T & and T tot .
  • Animals were treated from 8 to 12 weeks of age as described in Materials and Methods.
  • A Representative plethysmographic traces showing the breathing pattern of Wt vehicle-treated, Wt LM22A-4- treated, Het vehicle-treated, and Het LM22A-4-treated mice.
  • B Comparison of the breathing frequency, T tot , T, and T & among all four treatment groups.
  • Fig. 11 illustrates TrkB phosphorylation deficits in Mecp2 Het mice are reversed by chronic treatment with LM22A-4.
  • Top Representative Western blots showing phosphorylated TrkB Y817 (p TrkB), full-length TrkB (TrkB-F), truncated TrkB (TrkB-T), and actin in medulla and pons samples from (left to right) Wt vehicle-treated, Wt drug-treated, Het vehicle- treated, and Het drug-treated mice.
  • FIG. 12 illustrates AKT phosphorylation deficits in the pons of Mecp2 Het mice are reversed by chronic treatment with LM22A-4.
  • Top Representative Western blots showing p- AKT, total AKT (AKT), p-ERK, total ERK (ERK), and actin in pons samples from (left to right in each blot) Wt+V, Wt+D, Het+V, and Het+D mice.
  • Fig. 13 illustrates AKT and ERK phosphorylation in the medulla.
  • administering includes dispensing, delivering or applying an active compound in a pharmaceutical formulation to a subject by any suitable route for delivery of the active compound to the desired location in the subject (e.g., to thereby contact a brain stem and forebrain neurons), including administration into the cerebrospinal fluid or across the blood- brain barrier, delivery by either the parenteral or oral route, intramuscular injection, subcutaneous or intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route.
  • routes of administration may include
  • intraperitoneal (i.p.) injection and/or via oral routes are intraperitoneal (i.p.) injection and/or via oral routes.
  • an "effective amount" of an agent or combination of agents is an amount sufficient to achieve a desired therapeutic or pharmacological effect, such as an amount that is capable of ameliorating biochemical and functional abnormalities associated with loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MeCP2).
  • An effective amount of an agent or combinatory therapy as defined herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the agent to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the active compound are outweighed by the therapeutically beneficial effects.
  • the tern "therapeutically effective amount” refers to that amount of a composition that results in amelioration of symptoms or a prolongation of survival in a patient.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of a disease or condition or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or condition, e.g., Rett syndrome.
  • patient and “subject” refer to any animal, including, but not limited to, humans and non-human animals (e.g., rodents, arthropods, insects, fish).
  • non-human animals e.g., rodents, arthropods, insects, fish
  • zebrafish e.g., zebrafish
  • non-human primates e.g., ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, canines, felines, aves, etc.
  • porcines e.g., zebrafish
  • caprines e.g., ovines
  • equines e.g., canines, felines, aves, etc.
  • the terms "subject suffering from Rett syndrome”, “subject having Rett syndrome” or “subjects identified with Rett syndrome” refers to subjects that are identified or diagnosed as having or likely having a loss-of-function mutation in the gene encoding the methyl-CpG binding protein MeCP2 gene, which causes Rett syndrome.
  • modulate refers to a change in the biological activity of a biologically active molecule. Modulation can be an increase or a decrease in activity, a change in binding characteristics, or any other change in the; biological, functional, or immunological properties of biologically active molecules.
  • in vitro refers to an artificial environment and to processes or reactions that occur within an artificial environment.
  • in vitro environments consist of, but are not limited to, test tubes and cell culture.
  • in vivo refers to the natural environment (e.g., an animal or a cell) and to processes or reaction that occur within a natural environment.
  • a "known therapeutic compound” refers to a therapeutic compound that has been shown (e.g., through animal trials or prior experience with administration to humans) to be effective in such treatment or prevention.
  • Treating" or “treatment” of a condition or disease includes: (1) preventing at least one symptom of the conditions, i.e. , causing a clinical symptom to not significantly develop in a mammal that may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its symptoms, or (3) relieving the disease, i. e. , causing regression of the disease or its clinical symptoms.
  • Treatment, prevention and ameliorating a condition can include, for example decreasing or eradicating a deleterious or harmful condition associated with Rett syndrome. Examples of such treatment include:
  • Cyano refers to the group -CN.
  • Halogen or "halo” refers to fluorine, bromine, chlorine, and iodine atoms.
  • Haldroxy refers to the group -OH.
  • Alkyl refers to a cyclic, branched or straight chain, alkyl group of one to eight carbon atoms.
  • alkyl includes reference to both substituted and unsubstituted alkyl groups. This term is further exemplified by such groups as methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, cyclohexyl, i-amyl, n-amyl, and hexyl.
  • Substituted alkyl refers to alkyl as just described including one or more functional groups such as aryl, acyl, halogen, hydroxyl, amido, amino, acylamino, acyloxy, alkoxy, cyano, nitro, thioalkyl, mercapto and the like. These groups may be attached to any carbon atom of the lower alkyl moiety.
  • “Lower alkyl” refers to Ci-C 6 alkyl, with C1-C4 alkyl more preferred.
  • Cyclic alkyl includes both mono-cyclic alkyls, such as cyclohexyl, and bi-cyclic alkyls, such as bicyclooctane and bicycloheptane.
  • “Fluoroalkyl” refers to alkyl as just described, wherein some or all of the hydrogens have been replaced with fluorine (e.g., -CF 3 or -CF 2 CF 3 ).
  • Aryl or “Ar” refers to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently, or linked to a common group such as an ethylene or methylene moiety.
  • the aromatic ring(s) may contain a heteroatom, such as phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-l -ethyl, thienyl, pyridyl and quinoxalyl.
  • aryl or “Ar” includes reference to both substituted and unsubstituted aryl groups.
  • the aryl group may be substituted with halogen atoms, or other groups such as hydroxy, cyano, nitro, carboxyl, alkoxy, phenoxy, fluoroalkyl and the like. Additionally, the aryl group may be attached to other moieties at any position on the aryl radical which would otherwise be occupied by a hydrogen atom (such as 2-pyridyl, 3-pyridyl and 4-pyridyl).
  • alkoxy denotes the group -OR, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined below.
  • acyl denotes groups -C(0)R, where R is alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, amino and alkylthiol.
  • Carbocyclic moiety denotes a ring structure in which all ring vertices are carbon atoms. The term encompasses both single ring structures and fused ring structures. Examples of aromatic carbocyclic moieties are phenyl and naphthyl.
  • Heterocyclic moiety denotes a ring structure in which one or more ring vertices are atoms other than carbon atoms, the remainder being carbon atoms. Examples of non- carbon atoms are N, O, and S. The term encompasses both single ring structures and fused ring structures. Examples of aromatic heterocyclic moieties are pyridyl, pyrazinyl, pyrimidinyl, quinazolyl, isoquinazolyl, benzofuryl, isobenzofuryl, benzothiofuryl, indolyl, and indolizinyl.
  • amino denotes the group NRR', where R and R' may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl as defined below or acyl.
  • R 1 and R 2 may be identical or different (e.g., both R 1 and R 2 may be halogen or, R 1 may be halogen and R 2 may be hydrogen, etc.).
  • Embodiments described herein relate to compositions and methods of treating pervasive development disorders, such as Rett Syndrome or autism spectrum disorder, in a subject. It was found that loss of function mutations in Mecp2, the gene mutated in Rett syndrome (RTT), disrupts the balance of excitation and inhibition between the forebrain and brainstem in mouse models of the disease.
  • pervasive development disorders such as Rett Syndrome or autism spectrum disorder
  • perturbations of circuit function within and between the forebrain and brainstem are at least partially responsible for the pathophysiology of pervasive development disorders, such as RTT, i.e., the combination of deficits (hypoactivity) in forebrain- mediated functions, such as cognition, social communication and motor control on the one hand, and dysregulation (hyperexcitability) of brainstem-mediated functions, such as breathing, on the other.
  • RTT pervasive development disorders
  • RTT mice exhibit reduced activity throughout the forebrain, including reduced activity in structures critical for sensorimotor processing, cognition, motor control and social communication. It was also found that treatment of RTT mice with a low, sub-anesthetic dose of an N-methyl-D- aspartate receptor (NMDAR) antagonist acutely reverses hypoactivity in forebrain circuits and significantly improves at least one measure of forebrain function, i.e., prepulse inhibition of acoustic startle without altering brainstem hyperactivity.
  • N-methyl-D- aspartate receptor N-methyl-D- aspartate receptor
  • the NMDAR antagonist can be administered to a subject having or suspected of having a pervasive development disorder, such as RTT or autism spectrum disorder, to prevent, ameliorate or reverse pathologies associated with MeCP2 loss by reversing forebrain hypoactivity.
  • a method for treating a pervasive development disorder, such as RTT can include administering an NMDAR antagonist to a subject such that when administered ameliorates the core neurological symptoms of a pervasive development disorder, such as RTT, by re-establishing the normal balance between excitation and inhibition within and between the forebrain and brainstem, respectively.
  • the NMDAR antagonist can include an agent capable of antagonizing, or inhibiting the action of, the N-Methyl-D-aspartate receptor.
  • NMDAR antagonists include, but are not limited to: NMDA site antagonists, such as DL- AP7 (DL-2-Amino-7-phosphonoheptanoic acid), DL-AP5 (DL-2-Amino-5-phosphonopentanoic acid), D-AP5 (D-(-)-2-Amino-5-phosphonopentanoic acid), L-AP5 (L-(+)-2-Amino-5- phosphonopentanoic acid), D-AP7 (D-(-)-2-Amino-7-phosphonoheptanoic acid), (ftS)-CPP (( «5')-3-(2-Carboxypiperazin-4-yl)-propyl- l-phosphonic acid), (R)-CPP (3-((R)-2-
  • the NMDAR antagonist is selected from Amantadine, AZD6765, Dextrallorphan, Dextromethorphan, Dextrorphan, Diphenidine, Dizocilpine (MK- 801), Ethanol, Eticyclidine, Gacyclidine, Ibogaine, Memantine, Methoxetamine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine, Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Remacemide, Delucemine, 8A-PDHQ, Aptiganel, HU-211, Remacemide, Rhynchophylline, Ketamine, 1- Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate' DCKA (5,7- dichlorokynurenic acid), Kynure
  • the NMDAR antagonist can be a low-trapping NMDAR channel blocker.
  • An example of a low-trapping NMDAR channel blocker is an arylalkyl- amine having the following formula:
  • Ar 1 and Ar 2 which may be the same or different, independently represent phenyl or phenyl substituted by one or more of amino, nitro, halogen, hydroxy, Ci-C 6 alkoxy, Ci-C 6 alkyl or cyano;
  • R 1 represents hydrogen, Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl
  • R 2 represents hydrogen or COCH 2 NH 2 ;
  • R 3 represents hydrogen or Ci-C 6 alkyl
  • R 2 represents hydrogen either one or both of Ar 1 and Ar 2 may also represent 2-, 3- or 4-pyridinyl and R 1 may also represent trihalomethyl;
  • NMDAR antagonists having the above noted formula include:
  • the compounds described above are basic compounds and may be used as such or pharmaceutically acceptable acid addition salts may be prepared by treatment with various inorganic or organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic, methanesulfonic or carbonic acids.
  • various inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic, methanesulfonic or carbonic acids.
  • the NMDAR antagonist can be a low-trapping NMDAR channel blocker having the following formula:
  • R 1 and R 2 are independently phenyl or 4-fluorophenyl
  • R 3 is hydrogen, CI -6 alkyl or methoxycarbonyl
  • R 4 is hydrogen or methyl; and pharmaceutically acceptable salts thereof or an active metabolite thereof.
  • the low-trapping NMDAR channel blocker can include 2-amino-N-(l ,2-diphenyl-l-methylethyl)acetamide (remacemide) or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) or its active metabolite.
  • active metabolites of remacemide examples include desglycinyl metabolites, such as FPL 12495 or ARL 12495AA, FPL 14331 , FPl 14465, FPL 15455, FPL 14991 , FPL 14981 , FPL 13592, and FPL 15112.
  • the active metabolite can be FPL 12495 or ARL 12495 AA.
  • the NMDAR antagonist can be administered in combination with a TrkB agonist (e.g., in a combination therapy) to treat a pervasive development disorder, such as RTT or autism spectrum disorder.
  • a TrkB agonist e.g., in a combination therapy
  • RTT mice exhibit increased activity, associated with synaptic hyperexcitability (measured electrophysiologically) in brainstem circuits critical for respiratory and autonomic control. Hyperexcitability in brainstem respiratory and autonomic circuits is associated with deficits in Brain Derived Neurotrophic Factor (BDNF) and reduced activation of its receptor, TrkB.
  • BDNF Brain Derived Neurotrophic Factor
  • TrkB TrkB
  • exogenous BDNF and the small molecule TrkB ligand, LM22A-4 acutely reverse synaptic hyperexcitability in these circuits and eliminate apneic breathing in vivo.
  • the phrase "combination therapy” embraces the administration of a NMDAR antagonists and a TrkB agonist as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • the NMDAR antagonist and the TrkB agonist can be formulated as separate compositions or in a single composition.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, in a substantially simultaneous manner.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, intraperitoneal routes, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intraperitoneal injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered by intraperitoneal injection or all therapeutic agents may be administered orally.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • “Combination therapy” also can embrace the administration of the therapeutic agents as described herein in further combination with other biologically active ingredients, known therapeutic compounds and/or non-drug therapies (e.g., surgery).
  • a TrkB agonist for use in a combination therapy with the NMDAR antagonist can include any agent capable of directly activating or indirectly promoting the activation of TrkB.
  • a TrkB agonist capable of directly activating TrkB can include TrkB activating antibodies (described in Qian et al., Novel agonist monoclonal antibodies activate TrkB receptors and demonstrate potent neurotrophic activities. J Neurosci 2006; 26:9394-9403 and US2010/0297115).
  • a TrkB agonist capable of directly activating TrkB can also include small molecules that function as direct and specific TrkB activating ligands, such as but not limited to 7,8-dihydroxyflavone (7,8-DHF) (described in Jang et al., A selective TrkB agonist with potent neurotrophic activities by 7, 8-dihydroxyflavone. Proc Natl Acad Sci USA 2010;
  • BDNF loop 2 domain mimetic LM22A-4 (described in Massa et al., Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal
  • the TrkB agonist is an agent that transactivates TrkB including but not limited to adenosine or an adenosine agonist such as COS 21680 described in Lee and Chao, Activation of Trk neurotrophin receptors in the absence of neurotrophins, Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3555-60).
  • BDNF Mature brain-derived neurotrophic factor
  • BDNF is a secreted protein that, in humans, is encoded by the BDNF gene.
  • BDNF acts via two receptors, the p75 neurotrophin receptor and the TrkB tyrosine kinase receptor.
  • TrkB agonist can include any agent capable of increasing BDNF activation of TrkB in a subject.
  • agents can include BDNF itself and known therapeutic compounds that promote endogenous BDNF production in a subject including but not limited to ampakines, inhibitors of BDNF gene repression, mixed lineage kinase inhibitors, and antidepressants.
  • ampakines can be allosteric modulators of the AMPA-receptor.
  • AMPA amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
  • AMPA glutamatergic receptors
  • glutamatergic receptors are molecules or complexes of molecules present in cells, particularly neurons, usually at their surface membrane, that recognize and bind to glutamate or AMPA.
  • the binding of AMPA or glutamate to an AMPA receptor normally gives rise to a series of molecular events or reactions that result in a biological response.
  • the biological response may be the activation or potentiation of a nervous impulse, changes in cellular secretion or metabolism, or causing cells to undergo differentiation or movement.
  • Allosteric modulators of the AMPA-receptor that can be used for practicing the methods described herein and methods of making these compounds are disclosed in U.S. Pat. Nos.
  • ampakine compound can include those compounds having the following general Formula I:
  • R 1 is a member selected from the group consisting of N and CH; m is 0 or 1 ;
  • R 2 is a member selected from the group consisting of (CR 8 2) n - m an d C n - m R 8 2(n-m)- 2, in which n is 4, 5, 6, or 7, the R 8 's in any single compound being the same or different, each R 8 being a member selected from the group consisting of H and Ci-C 6 alkyl, or one R 8 being combined with either R 3 or R 7 to form a single bond linking the no. 3' ring vertex to either the no. 2 or the no. 6 ring vertices or a single divalent linking moiety linking the no. 3' ring vertex to either the no. 2 or the no.
  • R 3 when not combined with any R 8 , is a member selected from the group consisting of H, d- alkyl, and d-d alkoxy;
  • R 4 is either combined with R 5 or is a member selected from the group consisting of H, OH, and d-d alkoxy;
  • R 5 is either combined with R 4 or is a member selected from the group consisting of H, OH, d- alkoxy, amino, mono(Ci-C6 alkyl)amino, di(d-d alkyl)amino, and CH 2 OR 9 , in which R 9 is a member selected from the group consisting of H, d-d alkyl, an aromatic carbocyclic moiety, an aromatic heterocyclic moiety, an aromatic carbocyclic alkyl moiety, an aromatic heterocyclic alkyl moiety, and any such moiety substituted with one or more members selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy, halo, amino, alkylamino, dialkylamino, and methylenedioxy;
  • R 6 is either H or CH 2 OR 9 ;
  • R 4 and R 5 when combined form a member selected from the group consisting of
  • R 10 is a member selected from the group consisting of O, NH and N(d-C 6 alkyl);
  • R 11 is a member selected from the group consisting of O, NH and N(d-d alkyl);
  • R 12 is a member selected from the group consisting of H and d-d alkyl, and when two or more R 12 's are present in a single compound, such R 12 's are the same or different;
  • p is 1 , 2, or 3 ;
  • R 7 when not combined with any R 8 , is a member selected from the
  • Ci-C 6 alkyl consisting of H, Ci-C 6 alkyl, and Ci-C 6 alkoxy.
  • a further class of ampakine compounds is those of Formula II:
  • R Z1 is either H, halo or CF 3 ;
  • R and R either are both H or are combined to form a double bond bridging the 3 and 4 ring vertices;
  • R Z4 is either H, Ci— C 6 alkyl, C 5 — C 7 cycloalkyl, C 5 — C 7 cycloalkenyl, Ph, CH 2 Ph, CH 2 SCH 2 Ph, CH 2 X, CHX 2 , CH 2 SCH 2 CF 3 , CH 2 SCH 2 CH— CH 2 , or
  • R is a member selected from the group consisting of H and Ci -C 6 alkyl.
  • a particularly preferred compound is 1 -(Quinoxalin-6-ylcarbonyl)piperidine, having the following structure:
  • Another particularly preferred compound is l-(l,4-benzodioxan-6- ylcarbonyl)piperidine, having the following structure:
  • ampakine is a compound of formula III:
  • R 1 is oxygen or sulfur
  • X is -Br, -CI, -F, -CN, -N0 2 , -OR, -SR, -NR 2 , -C(0)R ⁇ , -C0 2 R, or -
  • R is hydrogen, Ci -C 6 branched or unbranched alkyl, which may be unsubstituted or substituted with one or more functionalities defined above as X, or aryl, which may be unsubstituted or substituted with one or more functionalities defined above as X;
  • n and y are independently 0, 1 or 2.
  • ampakine compounds described above for use in the methods described herein can be prepared by conventional methods known to those skilled in the art of synthetic organic chemistry as described in US Pat Pub No: 20100035877A1.
  • AMPA selective compounds capable of increasing BDNF activation of TrkB in a subject include AMPA selective compounds that enhance the stimulation of AMPA receptors and BDNF expression in the brain stem.
  • AMPA selective compounds for use herein include but are not limited to benzoxazines, such as the pyrolidine derivative racetam drugs piracetam and aniracetam, the CX- series of drugs which encompass a range of
  • benzoylpiperidine and benzoylpyrrolidine structures such as CX-546, CX-614, CX-691, CX- 717, Org 26576, CX-701, CX-1739, CX-1763 and CX-1837, benzothiazide derivatives such as cyclothiazide and IDRA-21, biarylpropylsulfonamides such as LY-392,098, LY-404, 187, LY- 451,646 and LY-503,430, 4-(benzofuran-5-yl carbonyl)morpholine, substituted
  • GABAR GABA receptor agonist
  • a GABAR agonist can include any agent that acts to directly or indirectly stimulate or increase the effect of the GABA receptor.
  • Exemplary GABAR agonists can include but are not limited to GABA analogs, such as Neurontin (Gabapentin), PD-0200, 390 (atagabalin) and Lyrica (pregabalin).
  • GABAR agonists can also include gamma-amino butyric acid A (GABA-A) agonists, gamma-amino butyric acid B (GABA-B) agonists and/or combinations thereof.
  • GABA-A agonists for use in the present invention can be selected from the benzodiazepine groups acamprosate, barbiturates, ethanol, methaqualone, muscimol, nonbenzodiazepines (zaleplon, Zolpidem, zopiclone), picamilon, progabide, and tiagabine.
  • Exemplary GABA-B agonists can be selected from 4-Amino-3-(4-chlorophenyl)butanoic acid ((RS)-Baclofen), (R)-4-Amino-3-(4-chlorophenyl)butanoic acid ((R)-Baclofen), CGP35024, CGP44532, 3-Aminopropyl(methyl)phosphinic acid (SKF 97541), 1 ,4-Butanediol, GBL ( ⁇ - Butyrolactone), GHB ( ⁇ -Hydroxybutyric acid), GHV ( ⁇ -Hydroxy valeric acid), GVL ( ⁇ - Valerolactone), lesogaberan, and phenibut.
  • GBL ⁇ - Butyrolactone
  • GHB ⁇ -Hydroxybutyric acid
  • GHV ⁇ -Hydroxy valeric acid
  • GVL ⁇ - Valerolactone
  • a pharmaceutical composition can include a therapeutically effective amount of an NMDAR antagonist alone and or in combination with a TrkB agonist and/or a GABAR agonist and a pharmaceutically acceptable diluent or carrier.
  • a combination therapy described herein can include the amount of a combination of therapeutic agents described herein effective to ameliorate biochemical and functional abnormalities associated with loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MeCP2) in a subject.
  • a therapeutically effective amount of an NMDAR antagonist can be the amount required to significantly improve at least one measure of forebrain function in a subject having Rett syndrome.
  • a therapeutically effective amount of an NMDAR antagonist can be the amount required to reverse hypoactivity in forebrain circuits of subjects having Rett syndrome.
  • a therapeutically effective amount of an NMDAR antagonist can be the amount of an NMDAR antagonist required to reverse abnormal synaptic phenotypes in the cortex of subjects having Rett syndrome such as deficits in mTOR signaling, decreased density of dendritic spines and/or abnormal E/I balance.
  • a therapeutically effective amount of a TrkB agonist can be the amount of a TrkB agonist required to measurably increase BDNF expression in the brainstem of a subject, the amount of a TrkB agonist required to measurably increase levels of TrkB phosphorylation in the brainstem of a subject, the amount required to acutely reverse synaptic hyperexcitability in brainstem respiratory and autonomic neural circuits in the subject, and/or the amount required to improve respiratory function in the subject, e.g., eliminate apneic breathing.
  • the administration of 50 mg/kg of LM22A-4 B.I.D for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild- type breathing frequency in a subject.
  • a therapeutically effective amount of a GABAR agonist can be the amount of a GABAR agonist required to measurably increase GABAergic signaling in a subject and/or the amount required to measurably increase synaptic transmission in brain regions important for respiratory control such as the ventrolateral medulla of a subject.
  • the therapeutic agents described herein are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms can be administered to the subject as part of a pharmaceutical composition for the treatment of a persuasive development disorder, such as Rett syndrome.
  • pharmaceutically acceptable carriers can be in any suitable form
  • Solid form preparations include, but are not limited to, powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the present invention contemplates a variety of techniques for administration of the therapeutic compositions.
  • Suitable routes include, but are not limited to, oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, among others. Indeed, it is not intended that the present invention be limited to any particular administration route.
  • the agents may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the carrier is a finely divided solid which is in a mixture with the finely dived active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions, which has been shaped into the size and shape desired.
  • the powders and tablets can contain from five or ten to about seventy percent of the active compounds.
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyleellulose, sodium earboxymethyleellulose, a low melting wax, cocoa butter and the like, among other embodiments (e.g., solid, gel, and liquid forms).
  • the term "preparation” is intended to also encompass the formation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active compound is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify in a form suitable for administration
  • Liquid form preparations include, but are not limited to, solutions, suspensions, and emulsions (e.g., water or water propylene glycol solutions).
  • emulsions e.g., water or water propylene glycol solutions
  • liquid preparations are formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, and stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyleellulose, sodium earboxymethyleellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methyleellulose, sodium earboxymethyleellulose, and other well- known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg/kg per day to about 100 mg/kg per day, for example, ranging from 10 mg/kg per day to about 50 mg/kg per day according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the quantity of an NMDAR antagonist in a unit dose preparation can be a sub-anesthetic dose.
  • the quantity of Ketamine in a unit dose can be a sub- anesthetic dose ranging from about 1 mg/kg to 20 mg/kg per day.
  • the quantity of Ketamine in a unit dose can be about 8 mg/kg per day.
  • the quantity of the NMDAR antagonist Remacemide in a unit dose can range from about 3 mg/kg to 120 mg/kg per day.
  • the quantity of a TrkB agonist LM22A-4 in a unit dose can range from about 50 mg/kg to 150 mg/kg per day.
  • the assessment of the clinical features and the design of an appropriate therapeutic regimen for the individual patient is ultimately the responsibility of the prescribing physician. It is contemplated that, as part of their patient evaluations, the attending physicians know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions. Conversely, the attending physicians also know to adjust treatment to higher levels, in circumstances where the clinical response is inadequate, while precluding toxicity.
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated, the patient's individual physiology, biochemistry, etc., and to the route of administration. The severity of the condition, may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and dose frequency will also vary according to the age, body weight, sex and response of the individual patient.
  • NMDA receptor (NMDAR) targeted therapies have utility for symptom reversal in RTT.
  • NMDAR NMDA receptor
  • ketamine in addition to its acute effects on cortical network activity, ketamine also rapidly stimulates dendritic growth, BDNF translation and expression of key synaptic proteins through activation of mTOR signaling, which is deficient in Mecp2 mutants (Fig.3).
  • Mecp2 L1Jae mice were purchased from the Mutant Mouse Regional Resource Center (University of California Davis, Davis CA) and maintained on a mixed genetic background (129Sv, C57BL/6, BALB/c) by crossing Mecp2 mL1Jae heterozygous females (Mecp A, Het) with Mecp2 L1Jae Wt males (Mecp2 + y ).
  • Free-floating 40 ⁇ sections were processed for Fos immunostaining by blocking with 10% goat serum in dilution buffer (PBS, BSA, 0.3% Triton X-100) for 1.5 h and then incubated overnight at room temperature (20 ⁇ 2 h) in rabbit polyclonal anti-c-Fos primary antibody (1 :3000, Calbiochem) in dilution buffer plus 10% goat serum. After sequential rinse steps in dilution buffer and PBS, sections were incubated in biotinylated goat anti-rabbit IgG secondary antibody (1 : 400, Vector Labs) in dilution buffer plus 15% goat serum for 1 h.
  • PBS dilution buffer
  • Triton X-100 Triton X-100
  • Fos-positive cells were neurons or astrocytes
  • a subset of sections were double stained with anti-c-Fos and either mouse anti-MAP2 (1 : 1000, Sigma) or mouse anti-GFAP (1 : 1000, Calbiochem), respectively.
  • Sections were visualized and photographed using an AxioSkop2 microscope (Zeiss) equipped with a Quantifire XI microscope camera (Optronics). Fos positive cells were counted using point by-point analysis with Neurolucida software (MBF Bioscience). Before analysis, the photomicrographs were coded so that the observers were blinded to the genotype. Cells were counted in every third section through the nTS, and in a representative subset of sections through the other brain regions analyzed. All sections were analyzed twice by two independent and blinded observers, and respective counts were averaged.
  • nTS was sampled at 12 levels through the rostro-caudal extent of the nucleus and the average counts at each level were then added together to estimate the total number of labeled cells per animal.
  • G*Power 3 power analysis software was used to determine group sizes.
  • FIG. 1 Horizontal brainstem slices were prepared from 3- and 5- to 7-week-old Mecp2 Null and Wt male mice. Animals were deeply anesthetized by inhalation of isoflurane and then decapitated. Brains were removed from the skull and placed in low Ca2+, ice-cold artificial CSF (ACSF) containing the following (in mM): 125 NaCl, 3 KC1, 1.2 NaH 2 P0 4 , 1 CaCl 2 , 1.2 MgS04, 2 MgCl 2 , 25 NaHC0 3 , 10 D-glucose, and 0.4 L-ascorbic acid, equilibrated to pH 7.4 with 95% 0 2 /5% C0 2 , for 2-5 min.
  • ACSF ice-cold artificial CSF
  • brainstems were dissected, glued on the mounting platform of a vibratome (Leica, VT 1000S), and horizontal sections containing the nucleus tractus solitarius (nTS), including a long segment of the tractus solitarius (TS) were cut at 220-250 ⁇ .
  • nTS nucleus tractus solitarius
  • TS tractus solitarius
  • Patch pipettes were pulled from thick-walled borosilicate glass capillaries, and filled with intracellular solution (containing in mM: 130 K_gluconate, 10 NaCl, 11 EGTA, 1 CaCl 2 , 10 HEPES, 1 MgCl 2 , 2 MgATP, 0.2 NaGTP), had resistances between 4 and 7 ⁇ .
  • nTS nTS at the level of, and caudal to the obex: (1) lateral to or within the TS, including the interstitial, lateral and ventrolateral subnuclei [referred to as lateral nTS (InTS)], (2) within the commissural subnucleus (nComm).
  • Neurons were visualized with an upright Olympus microscope (BX51WIF). Cells were identified as second-order neurons if they received monosynaptic input, defined as a low jitter of latency of evoked postsynaptic responses ( ⁇ 25( s), at 0.5 Hz TS stimulation.
  • Evoked, spontaneous and miniature EPSCs were recorded from cells meeting this criterion in the whole-cell voltage-clamp configuration at a holding potential of -60 mV.
  • the TS was stimulated at 0.5 and 20 Hz.
  • input- output curves were obtained by gradually increasing the stimulus intensity based on the neurons' individual threshold (thrsh, thrsh + 10%, thrsh + 50%, 2X thrsh, 5X thrsh).
  • the stimulation intensity was set to threshold + 10%, typically between 50 and 200 ⁇ (stimulus duration 100 ⁇ 8, 20 sweeps).
  • nComm neurons To compare intrinsic neuronal excitability between genotypes, action-potential properties and firing frequency in response to current injection (50 pA increments) were recorded in nComm neurons as well. Only neurons with a resting membrane potential of at least -40 mV upon breakthrough were accepted. Data were acquired using pClamp software. Signals were amplified (Axopatch 200B, Molecular Devices), filtered at 2 kHz and digitized at 10 kHz.
  • Prepulse inhibition (PPI) of the acoustic startle response (ASR) was measured to assess sensorimotor gating function using Med Associates Startle Response recording system. Mice were divided into four groups (Het ketamine, Het vehicle, Wt ketamine, Wt vehicle), and received injectionsof either ketamine (8 mg/kg) or an equivalent amount of saline immediately before they were placed individually inside a small-sized, nonrestrictive, cubical Plexiglas recording chamber [2.5 inches (L) X 2.5 inches (W) X 1.75 inches (H)] fixed on an accelerometer platform and allowed to acclimate for 5 min. Subsequently, the mouse was exposed to 4 testing blocks.
  • the initial startle response amplitude was determined by delivering a 40 ms pulse of 120 dB broadband white noise and recording the maximum startle amplitude (Vmax).
  • Vmax maximum startle amplitude
  • a baseline startle response was determined by repeating this recording paradigm for six consecutive trials (with 8-23 s between each stimulus) and calculating the average Vmax measured in those trials.
  • the mice were exposed to a series of "pulse-only" or "prepulse-pulse pair" stimuli to determine the effect that a reduced intensity prepulse had on the acoustic startle response.
  • the pulse-only stimulus consisted of an 80 ms stimulus of 120 dB.
  • the prepulse-pulse pair trials were conducted by delivering a single 20 ms prepulse, with an intensity of 73, 76 or 82 dB before an 80 ms stimulus with an intensity of 120 dB. An average delay of 15 s (8-23 s) occurred between each stimulus. Each prepulse-pulse pair trial was repeated 10 times, pulse only trials were repeated 12 times. The Vmax measured from each prepulse-pulse trial was compared with the Vmax measured from the 120 dB pulse-only trials, and a percentage prepulse inhibition ( PPI) was calculated for each prepulse intensity.
  • PPI percentage prepulse inhibition
  • startle response Vmax was recorded from 6 additional 40 ms pulses of 120 dB broadband white noise (with 8-23 s between each stimulus) and compared with the baseline startle response from the first testing block to eliminate the possibility of habituation to the acoustic stimulus throughout the test.
  • Fos immunostaining has been widely used as a surrogate marker of neuronal depolarization to map circuits and pathways in the normal brain that are activated by specific types and patterns of neural stimulation. Given that excitatory-inhibitory imbalance has been documented within various cell groups in the Mecp2 mutant brain, we hypothesized that Wt and Null animals would exhibit regional differences in Fos expression and that these differences could be used to map sites of circuit dysfunction in the Null brain.
  • the Null PAG had significantly fewer Fos-positive cells compared with Wt (Wt, 38.1+20.0; Null, 25.1+6.0; p ⁇ 0.0 ⁇ ; Table 1; Fig. IF).
  • Null mice exhibited significantly more Fos-positive cells throughout the rostrocaudal extent of the three major cardiorespiratory subnuclei in nTS [medial (mnTS), commissural (nComm) and lateral nTS, including interstitial, lateral and ventrolateral subnuclei (InTS)] compared with Wt (%Wt; mnTS; 306.5%; nComm; 245.0%, InTS; 324.8%; Fig. 2A-C; Table 1).
  • Wt %Wt; mnTS; 306.5%; nComm; 245.0%, InTS; 324.8%; Fig. 2A-C; Table 1).
  • nRA nucleus retroambiguus
  • pBC preBotzinger complex
  • pontine nucleus or the cerebellum
  • Piriform cortex 266.3 + 35.0 124.2 + 19.7 *
  • the cumulative mEPSC amplitude distribution curve also displayed a significant right shift in the Nulls, indicating larger mEPSC amplitudes (Kolmogorov- Smirnov test, p ⁇ 0.05, Fig. 4E).
  • We did not observe genotype differences in mEPSC rise or decay times rise time; Wt, 1.00 + 0.11 ms; Null, 0.91 + 0.09 ms; decay time; Wt, 2.91 + 0.49 ms; Null, 2.75 + 0.36 ms).
  • Fos induction was strongest in the prelimbic, infralimbic, piriform, cingulate and retrosplenial cortices (Fig. 6).
  • Quantitative analysis of Fos labeling in the piriform cortex revealed a dosedependent effect of ketamine on the number of Fos-positive cells in the Nulls, including restoration of Wt levels at higher doses (Null vehicle, 41.3 + 9.2 cells; Null 8 mg/kg ketamine, 82.9 +_ 13.4 cells; Null 20 mg/kg ketamine, 83.2 + 18.2 cells; Null 100 mg/kg ketamine, 116.3 + 26.4 cells; Wt vehicle, 99.5 + 13.3 cells; Wt 100 mg/kg ketamine, 119.3 + 17.2 cells; Fig. 6C). These data indicate that although Fos is downregulated in limbic forebrain structures in the absence of MeCP2, Fos expression remains plastic and subject to induction by factors that alter forebrain network activity.
  • PPI of the ASR is a measure of sensorimotor gating and is widely used as an index of cognitive function in neuropsychiatric disorders, including ASDs.
  • PPI measures the ability of a weak sensory input to modulate behavioral responses to a subsequent strong sensory stimulus and thereby reflects the function of inhibitory circuitry thought to be critical for normal cognition. Because the circuitry underlying PPI includes structures that exhibit reduced Fos staining in Nulls, such as the mPFC and nAC and because ketamine treatment of Nulls rescues Fos expression in these regions, we decided to use PPI as an index of forebrain circuit function in the absence and presence of ketamine.
  • Hets Heterozygous female Mecp2 mutants
  • acoustic startle measurements can be unreliable in Nulls due to their relatively small size.
  • overall levels of Fos expression are lower in females compared with males
  • Fos was significantly reduced in the Het forebrain compared with Wt, as in male Nulls (Table 3).
  • Acute treatment with ketamine restored PPI in Hets to Wt levels (Het ketamine, PPI 73 dB, 5.3+5.8; %PPI 76 dB, 17.8+2.9; PPI 82 dB, 21.4+6.4, Fig. 7), whereas ketamine treatment did not alter PPI in Wt (Wt ketamine, PPI 73 dB, 7.8+4.1 ; PPI 76 dB, 12.8+4.8; %PPI 82 dB, 24.1+5.8; Fig. 10) and had no effect on acoustic startle alone (Wt ketamine, 798.6+106.3; Het ketamine, 862.7 + 149.5).
  • LM22A-4 which functions as a direct and specific partial agonist of TrkB, but not p75, to increase TrkB activation and improve breathing in a mouse model of RTT.
  • LM22A-4 was developed by in silico screening for mimetics of BDNF loop domains that selectively activate TrkB in vitro and in vivo and promote recovery of motor function in a rodent model of brain trauma. Using heterozygous female Mecp2 mutant mice, we show that daily treatment with LM22A-4 is well tolerated and rescues wild-type levels of TrkB phosphorylation and wild-type breathing frequency.
  • Mecp2tm ⁇ AJae mice were purchased and maintained on a mixed background (129Sv, C57BL/6, BALB/c) by crossing Mecp2 tmLUae heterozygous females (Mecp2 / + , Het) with Mecp2 tin ' ae wild-type males (Mecp2 + / V ). Experimental procedures were approved by the Institutional Animal Care and Use Committee at Case Western Reserve University.
  • BDNF ELISA assay (Promega) according to the manufacturer's protocol. The sensitivity of this BDNF ELISA assay is- 1-3 pg BDNF/ml. Brain tissues and nodose ganglia were rapidly dissected and quick-frozen on dry-ice. Brain tissue samples were homogenized in 200 ⁇ of RIPA buffer (containing, in mM: 50 Tris-HCl, 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 NaCl, 1 EDTA, pH 7.4) containing a mixture of protease inhibitors (Roche), and centrifuged at 16,000 x g for 15 min at 4°C.
  • RIPA buffer containing, in mM: 50 Tris-HCl, 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 NaCl, 1 EDTA, pH 7.4
  • protease inhibitors (Roche), and centrifuged at 16,000 x g for 15 min at 4°C.
  • Nodose ganglia were homogenized in 100 ⁇ of the same buffer and centrifuged at 14,000 x g for 30 s at room temperature. The supernatant from each sample was collected and stored at -80°C until further use. For brain tissue samples, an aliquot of the supernatant was used to determine total protein content using the Bradford technique and 300 ⁇ g of total protein were used for BDNF ELISA. For BDNF ELISA, the entire supernatant from each individual nodose ganglion was loaded.
  • TrkB full-length
  • LM22A-4 custom synthesized by Ricerca Biosciences, LLC
  • LC-MS/MS triple-quadrupole tandem mass spectrometric
  • Atenolol a drug that does not cross the blood- brain barrier, was administered orally as a control to correct for contamination by blood present in the brain vascular space.
  • Brainstem and forebrain samples were homogenized with a Virsonic 100 ultrasonic homogenizer and prepared for analysis using acetonitrile precipitation by combining one volume of sample with three volumes of acetonitrile.
  • the analyte was eluted with a gradient which changed linearly from 0 to 100% B in 3 min at a flow rate of 300 ⁇ /min. The total run time was 4.5 min and the injection volume was 10 ⁇ .
  • the analyte was detected on a Sciex API 3000 triple-quadrupole mass spectrometer equipped with a TurboIonSpray interface in the positive electrospray ionization mode (Applied Biosystems/MDS).
  • the multiple reaction monitoring transitions and instrument settings were optimized for LM22A-4. Equipment operation, data acquisition, and data integration were performed using Analyst version 1.4.2. software (Applied Biosystems).
  • the drug injections, tissue extraction and LCMS/ MS analysis were performed by Absorption Systems.
  • Respiratory patterns were analyzed at 8, 10, and 12 weeks after birth in unrestrained mice using whole -body plethysmography as described previously. Measurements were taken from quiet breathing periods of at least 5 min total duration, and apneas were defined as pauses in breathing greater than two times the average breath duration calculated for each animal. LM22A-4 treatment.
  • Wt and Het littermates were divided into 4 groups: Wt vehicle-treated (100 ⁇ of 0.9% NaCl, i.p., b.i.d.), Wt drug treated (50 mg/kg LM22A-4 in 0.9% NaCl, i.p., b.i.d.), Het vehicle-treated (100 ⁇ of 0.9% NaCl, i.p., b.i.d.), and Het drug-treated (50 mg/kg LM22A-4 in 0.9% NaCl, i.p., b.i.d.).
  • Each mouse was treated from 8 to 13 weeks of age. Whole-body plethysmography was performed during week 12 and animals were subsequently killed and tissues harvested for TrkB Western blots and BDNF ELISA during week 13.
  • Mecp 2tml Uae -null mice exhibit deficits in BDNF expression in structures critical for respiratory control, including the cranial sensory nodose ganglion (NG) and brainstem.
  • NG cranial sensory nodose ganglion
  • Fig. 9 BDNF protein levels in these regions in Wt and Het mice at 8, 10, and 12 weeks of age.
  • BDNF levels in the Het NG were significantly below Wt at all 3 ages (Fig. 9A). Accordingly, we found reduced immunostaining for BDNF in the medullary nucleus tractus solitaries (nTS), the primary target of afferent projections from NG sensory neurons to the brainstem (Fig.
  • LM22A-4-treated Hets In contrast to vehicle-treated Het controls, LM22A-4-treated Hets exhibited values of breathing frequency, T & and T tot that were not significantly different from those of Wt (Fig. 10A,B; pooled results of 4 independent experiments). The percentage of apneic animals was unaffected by drug treatment (data not shown), and there were no significant differences in respiratory function between vehicle- and drug-treated Wt mice. Moreover, drug treatment had no effect on body weight in either Wt or Het mice throughout the treatment period (Fig. IOC).
  • LM22A-4 treatment reverses TrkB phosphorylation deficits in the brainstem of Het mice
  • TrkB/actin TrkB-T/actin, respectively.
  • Pons and medulla samples from vehicle-treated (control) Hets exhibited significant decreases in p-TrkBY817/TrkB and p-TrkBY817/actin compared with vehicle treated (control) Wt animals with no change in the levels of total full- length TrkB or truncated TrkB.
  • TrkB phosphorylation in Het mice were completely reversed by treatment with LM22A-4 (Fig. 11).
  • drug-treated Hets showed significantly higher levels of p-TrkB/TrkB and p-TrkB/actin than wild-type controls in the pons.
  • TrkB phosphorylation was reflected in changes in phosphorylation of the serine/threonine protein kinase AKT (p- AKT) and extracellular signal regulated kinase ERK MAPK (p-ERK), key downstream mediators of the biological effects of TrkB activation.
  • p- AKT serine/threonine protein kinase AKT
  • p-ERK extracellular signal regulated kinase ERK MAPK
  • TrkB pharmacologic activation of TrkB in Mecp2 Het mice eliminates respiratory tachypnea supports the role of BDNF/TrkB signaling deficits in respiratory dysfunction in RTT and provides proof-of-concept for the therapeutic potential of TrkB agonists to improve this and other aspects of the disease.
  • our data demonstrate the ability of a BDNF loop domain mimetic to enhance TrkB activation and restore wildtype respiratory frequency in Mecp2 Het mice.

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HK1217896A1 (zh) 2017-01-27
EP2948135B1 (de) 2019-01-02
US10555916B2 (en) 2020-02-11
US20150359759A1 (en) 2015-12-17

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